ABSTRACT/PROJECT SUMMARY Preterm birth is the leading cause of pediatric morbidity and mortality worldwide, with catastrophic health outcomes and significant economic implications. In spite of increasing survival, children born preterm continue to suffer suboptimal outcomes when compared to their full-term born counterparts. One of the common underpinnings associated with life-limiting health outcomes of the preterm infant is immature immune- regulation and an exaggerated inflammatory response. The preterm infant gut and brain are especially vulnerable to inflammation, as evidenced by multiple studies that have reproducibly shown that higher levels of inflammatory proteins measurable in the urine and blood as early as the first four weeks following birth are associated with both short and long-term intestinal and neurological health. Maternal breast milk (MBM) is known to be immuoprotective during infancy. However, little is known about the newly discovered milk microbiome following preterm birth, and the direct influence this may have on measures of intestinal or systemic inflammation. In this study, we will test our overall hypothesis that the taxa comprising the community structure of the milk microbiome influences measures of intestinal and systemic inflammation of the preterm infant during the early neonatal period. We will collect MBM, infant urine and blood samples from preterm mother-infant pairs at four study time points (1, 2, 4 weeks of age, and 36 weeks adjusted gestational age). 16s rRNA sequencing will define the community structure of the milk microbiome. Whole genome sequencing will identify species level taxa and bacterial functional potentials (genes and metabolic pathways) in infants who have the highest and lowest measures of inflammation assessed by levels of inflammatory proteins including urinary intestinal fatty acid binding protein (iFABP), and serum-based CRP, IL1?, IL6, IL8, ICAM-1. Defining the milk microbiome in the context of intestinal and systemic inflammation among preterm infants who are vulnerable to long-term impairment associated with immune regulated disease will build the scientific foundation for novel interventions that seek to therapeutically enrich enteral sources of infant nutrition. These interventions will have the potential to attenuate the inflammatory response of the preterm infant, thereby preventing disease and disability across the lifespan.